Cystic fibrosis (CF) is a monogenic genetic disorder caused by mutations in CFTR, and respiratory disease is the major cause of morbidity and mortality. The median age of survival in CF is only 37 years, but there is a broad range of disease severity in the lung, even among patients with identical CFTR genotypes, including ?F508 homozygotes. Robust twin/sib studies conclude that genetic factors must play a critical role in disease severity. Two transformational studies of twins and sibs assessed environmental versus genetic influences, and both concluded that genetic factors play a major, or even majority, role in lung disease severity, and heritability estimates ranged from 0.54 to 0.89. Early candidate gene studies to identify CF modifiers were limited by small sample size and poorly defined phenotypes. These limitations have been addressed by a North American CF Genetic Consortium, which includes study groups at UNC/CWRU, Johns Hopkins, and Toronto. Genetic Modifier Consortium patients are now being tested in a whole-genome scan (Illumina 610K Quad). This RFA now provides the opportunity to study the role of gene expression variation in CF lung disease, and the integrated analysis of SNPs/CNVs and expression data. This project holds great promise for defining a robust molecular phenotype for CF lung disease, and we will be uniquely positioned to develop an integrated view of molecular mechanisms underlying CF lung disease severity. Since most CF patients are now diagnosed by neonatal screening, each CF patient could have a molecular signature, and associated risk, established early in life. Taken together, expression data and whole genome SNP data in the same CF patients are likely to spawn a variety of biological and clinical research activity in CF (and other) lung diseases, and provide unprecedented opportunities for novel prognostic and therapeutic interventions in CF. The identification of molecular mechanisms relevant to lung disease severity in CF is also likely to be relevant to more common lung diseases, such as asthma and COPD, as has already been shown for variants and differential gene expression in TGF[unreadable]1.